Chronic lymphocytic leukemia is the most common adult leukemia in Western societies with 10,000 cases diagnosed in the United States every year and a prevalence of approximately 80,000 cases (US Estimated 28-Year Limited-Duration Prevalence on 1/1/2003) (http://seer.cancer.gov/). Although much has been learned about the genetics, biochemistry and immunology of this disease, CLL still is considered incurable, mandating development of improved treatment strategies. Like other cancers, CLL cells harbor genetic changes that apparently play a role in the pathogenesis or progression of this disease. Such alterations, along with the clonal expression of somatically generated immunoglobulin genes, may direct expression of "altered-self" proteins that could be targeted by the patient's immune system. Strategies that can induce such immune responses against autologous leukemia cells may be effective in the treatment of this disease. The investigators propose to evaluate the pre-clinical and clinical activity of a new modality of immuno-gene therapy mediated by transduction of leukemia cells with CD154 (CD40 Ligand) using direct intra-lymph node (intranodal) injection of a replication-defective adenovirus vector that encodes a chimeric (human-mouse) CD154 molecule (Ad-ISF35). Direct intranodal injection of Ad-ISF35 may prove to be an effective and less expensive strategy to transduce cancer cells and induce anti-tumor responses compared with the current protocols that we are using in which ex-vivo manipulation of the leukemia/ lymphoma cells is required. The support obtained from this grant will facilitate Phase 1 clinical data that is essential for the development of this therapeutic strategy in CLL and its potential applications to other types of cancer.